Anthracyclinones

ABSTRACT

There is presented a synthetic process for the production of anthracyclinones, the aglycones of the anthracyclines. Also disclosed are novel intermediates in the above process. The end product aglycones may thereafter be utilized to produce biologically useful products such as carminomycin or adriamycin.

This is a division of application Ser. No. 139,532, filed Apr. 11, 1980,now U.S. Pat. No. 4,264,510.

DESCRIPTION OF THE INVENTION

The present invention is concerned with a novel synthetic approach toanthracyclinones, the aglycones of the anthracyclines, especially withthe use of the known 2,3,5,6-tetramethylene-7-oxabicyclo[2.2.1]heptane(I, Tetrahedron Lett. 1976, 4271) for their manufacture and novelpolycyclic compounds which are obtained as intermediates.

The process provided by the invention comprises reacting2,3,5,6-tetramethylene-7-oxabicyclo[2.2.1.]-heptane (I) with a suitabledienophile to give1,2,3,4,8a,10,10a-octahydro-2,3-dimethylene-1,4-epoxyanthracene-5,8-dione(II), 1,2,3,4,9,10-hexahydro-2,3-dimethylene-1,4-epoxyanthracene (III)or a compound of the general formula ##STR1## wherein R² represents amethyl or lower alkoxy group, if desired, isomerising the compound II inthe presence of catalytic amounts of an acid or base to give1,2,3,4,9,10-hexahydro-5,8-dihydroxy-2,3-dimethylene-1,4-epoxyanthracene(V) and methylating this compound V to give1,2,3,4,9,10-hexahydro-5,8-dimethoxy-2,3-dimethylene-1,4,-epoxyanthracene(VI), or reducing the compound II to give a compound of the formula##STR2## converting this compound XX into a compound of the formula##STR3## and, if desired, etherifying this compound XXI to give acompound of the general formula ##STR4## wherein R³ represents a methylor benzyl group, if desired, reacting a compound of the general formula##STR5## wherein R¹ represents a hydrogen atom or a hydroxy or methoxygroup and R⁴ represents a hydrogen atom or a hydroxy, methoxy orbenzyloxy group,

with a suitable dienophile in a diene synthesis to give a compound ofthe general formula ##STR6## wherein R¹, R² and R⁴ have the significancegiven earlier, if desired, reacting a resulting compound of the formulaIV with 1,4-benzoquinone or dehydrobenzene in a diene synthesis to givea compound of the general formula ##STR7## wherein R² has thesignificance given earlier, if desired, isomerising a compound IX in thepresence of catalytic amounts of an acid or base to give a compound ofthe general formula ##STR8## wherein R² has the significance givenearlier, and methylating this compound XI to give the correspondingdimethoxy compound of the general formula ##STR9## wherein R² has thesignificance given earlier, if desired, dehydrogenating a compound offormula VII or VIII to give a compound of the general formula ##STR10##wherein R¹, R² and R⁴ have the significance given earlier, or, ifdesired, reacting a compound of formula XIII with a suitable dienophilein a diene synthesis to give a compound of the formula XIV, if desired,opening the epoxide ring present in a compound of formula XIV andacetylating the resulting mixture of the corresponding 5- and 12-hydroxycompounds, if desired after prior oxidation to a compound of the generalformula ##STR11## wherein R¹, R² and R⁴ have the significance givenearlier, to give a compound of the general formula ##STR12## wherein R¹,R² and R⁴ have the significance given earlier and Ac represents anacetyl group,

and, if desired, oxidising this compound of formula XVI to give aquinone of the general formula ##STR13## wherein R¹, R², R₄ and Ac havethe significance given earlier.

The key reaction of the synthesis provided by the present invention isthe reaction of the compound I with a suitable dienophile to give acompound II, III or IV. Suitable dienophiles are 1,4-benzoquinone,dehydrobenzene, methyl vinyl ketone and derivatives thereof such as H₃C--COO--C(═CH₂)--CO--CH₃, C₆ H₅ --COO--C(═CH₂)--CO--CH₃ or (H₃ C)₃SiO--C(═CH₂)--CO--CH₃, or acrylic acid lower alkyl esters, the methylester being preferred.

The reaction is carried out in a manner known per se under theconditions of a Diels-Alder addition using equimolar amounts of thediene and of the dienophile. The reaction gives high yields of thesterically correct product. The dehydrobenzene is generated in situ in aknown manner (e.g. from anthranilic acid).

The isomerisation of the resulting1,2,3,4,8a,9,10,10a-octahydro-2,3-dimethylene-1,4-epoxyanthracene-5,8-dione(II) to give the corresponding 5,8-dihydroxy compound V and theetherification of the latter to give1,2,3,4,9,10-hexahydro-5,8-dimethoxy-2,3-dimethylene-1,4-epoxyanthracene(VI) can be carried out in a manner known per se by treatment with asmall amount of an acid or base (e.g. silicic acid) and subsequentmethylation (e.g. with methyl iodide).

Both reactions can be carried out with almost quantitative yield also inone step by treating the compound II with for example, methyl iodide inthe presence of potassium carbonate.

The reduction of the 5,8-dione of formula II to give the8-hydroxyanthracen-5-one of formula XX can be carried out in a mannerknown per se by treatment with an equivalent amount of a complex hydride(e.g. diisobutyl aluminium hydride, lithium aluminium hydride ortetra-n-butylammonium borohydride) in an inert organic solvent. Thereduction can also be carried out with sodium borohydride and ammoniumchloride, although in this case somewhat lower yields of the desiredproduct are obtained.

The dehydration of the 8-hydroxyanthracen-5-one of formula XX to givethe anthracen-5-ol of formula XXI is conveniently effected by mesylationor tosylation and subsequent cleavage of methanesulphonic acid ortoluenesulphonic acid in a manner known per se using a base, withsimultaneous aromatisation of the A-ring. Finally, by methylation orbenzylation in the usual manner there is obtained the correspondingmethyl or benzyl ether of formula XXII.

Now, in optional sequence, a compound of formula VII obtained can bearomatised in ring B and subjected to a further Diels-Alder addition.The dehydrogenation can be carried out, for example, using anappropriately substituted quinone such as2,3-dichloro-5,6-dicyano-1,4-benzoquinone or chloranil in an inertsolvent. Suitable dienophiles which can be used for the furthersynthesis of the polycyclic system include acrylic acid esters,preferably methyl acrylate, or methyl vinyl ketone or the previouslymentioned derivatives thereof. There is thus obtained from a compoundVII either firstly a compound XIII which is then converted into acompound XIV by Diels-Alder addition, or a compound VIII which can thenbe dehydrogenated to give compound XIV.

On the other hand, a compound of the formula IV can be converted into acompound IX or X by Diels-Alder addition of 1,4-benzoquinone ordehydrobenzene in a manner known per se and analogously to theaforementioned conversion of compound I into compound II or compoundIII.

The compound IX can be isomerised to give a compound XI which can thenbe methylated to give compound XII in analogy to the conversion ofcompound II into compound V and conversion of the latter into compoundVI.

A 5,12-epoxy compound XIV can be converted, with opening of the epoxidering, into a mixture of the corresponding 5- and 12-hydroxy compounds bytreatment with an acid (e.g. trifluoroacetic acid) in an inert organicsolvent (e.g. chloroform or benzene). If this treatment is carried outin the presence of acetic anhydride, then there is obtained a mixture ofcorresponding 5- and 12-acetoxy compounds. The mixture can be separatedby chromatography, although this is not essential for the further courseof the synthesis because by using Tl(OAc)₃.11/2H₂ O as the acetylatingagent at room temperature in the presence of acetic anhydride there isobtained from the mixture of the 5- and 12-hydroxy compounds the5,12-diacetoxy compound XVI. On the other hand, the mixture of the 5-and 12-hydroxy compounds can be oxidised, for example, with PbO₂ oratmospheric oxygen in an acid medium, preferably acetic acid, at roomtemperature, to give the quinone of formula XV which can then bereductively acetylated to give the 5,12-diacetoxy compound XVI. This canbe carried out, for example, by heating to reflux for a short time withzinc dust in acetic anhydride.

Finally, a compound XVI can be converted into a compound XVII in amanner known per se by oxidation with an oxidation agent such as chromicacid in acetic acid at room temperature.

The compounds of formulae II-XVI and XX-XXII are novel compounds andalso form part of the present invention, while compounds of formula XVIIare already known and can be converted in a known manner intobiologically active anthracyclines; for example, via the followingintermediates:

The novel aglycones of the present invention can be converted intopharmaceutically useful end products by following methods well-known inthe art, for example, the following steps:

(a) Introduction of hydroxy group in position 9: Cava et al., J. Am.Chem. Soc. 100, 3635 (1978),

(b) Introduction of hydroxy group in position 7: Wong et al., Can. J.Chem. 49, 2712 (1971),

(c) Glycosylation: Annual reports in Medicinal Chemistry, Vol. 14,Editor H. J. Hess, Academic Press, New York, San Francisco, London,1979, p. 288 (Synthetic Approaches to Anthracycline Antibiotics).##STR14##

The following Examples illustrate the present invention.

EXAMPLE 1

A mixture of 2 g (13.7 mmol) of2,3,5,6-tetramethylene-7-oxabicyclo[2.2.1]heptane, 1.47 g (13.7 mmol) offreshly sublimed p-benzoquinone and 20 ml of chloroform was heated at80° C. for 5 hours under nitrogen. After cooling, the mixture wasconcentrated to dryness and recrystallised from acetone/methanol (4:1).There were obtained 3.28 g (95%) of1,2,3,4,8a,9,10,10a-octahydro-2,3-dimethylene-1,4-epoxyanthracene-5,8-dioneof melting point 147° C. (decomposition) in the form of yellow crystals.

11.21 g (79 mmol) of methyl iodide were added dropwise under nitrogen toa mixture of 2 g (7.9 mmol) of1,2,3,4,8a,9,10,10a-octahydro-2,3-dimethylene-1,4-epoxy-anthracene-5,8-dione,10.9 g (79 mmol) of dried potassium carbonate and 100 ml of anhydrousacetone. The mixture was heated at 80° C. for 15 hours, filtered, thefiltrate was concentrated, the residue was taken up in 80 ml ofchloroform and the solution was washed with three 40 ml portions ofwater. After drying over magnesium sulphate, concentration andrecrystallisation from diethyl ether/tetrahydrofuran/methylene chloride(4:1:2), there were obtained 2.05 g (92%) of1,2,3,4,9,10-hexahydro-5,8-dimethoxy-2,3-dimethylene-1,4-epoxyanthraceneof melting point 177°-178° C. in the form of white crystals.

A mixture of 2 g (7.1 mmol) of1,2,3,4,9,10-hexahydro-5,8-dimethoxy-2,3-dimethylene-1,4-epoxyanthracene,1.77 g (7.8 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 30 mlof benzene was stirred at room temperature under nitrogen for 30minutes. The precipitate formed was filtered off and washed withbenzene, the benzene solution was washed with two 30 ml portions ofsaturated aqueous sodium hydrogen sulphite solution and two 30 mlportions of water, dried over sodium sulphate and concentrated todryness. By recrystallisation from diethylether/tetrahydrofuran/methylene chloride (4:1:2) there were obtained1.95 g (98%) of1,2,3,4-tetrahydro-5,8-dimethoxy-2,3-dimethylene-1,4-epoxyanthracene ofmelting point 205°-206° C. in the form of white crystals.

A mixture of 3 g (10.7 mmol) of1,2,3,4-tetrahydro-5,8-dimethoxy-2,3-dimethylene-1,4-epoxyanthracene and30 ml of methyl vinyl ketone was heated at 90° C. for 24 hours undernitrogen. Excess methyl vinyl ketone and oligomer formed by the heatingwere removed by distillation at 110° C. under reduced pressure (10⁻²mmHg). The residue was recrystallised from tetrahydrofuran/methylenechloride/hexane (3:3:5) and yielded 3.5 g (93%) of(1,2,3,4,5,12-hexahydro-7,10-dimethoxy-5,12-epoxynaphthacen-2-yl) methylketone of melting point 167°-168° C. in the form of a white amorphouspowder.

0.2 ml of trifluoroacetic acid was added under nitrogen to a solution of1 g (2.9 mmol) of(1,2,3,4,5,12-hexahydro-7,10-dimethoxy-5,12-epoxynaphthacen-2-yl) methylketone in 10 ml of chloroform. The mixture was stirred at roomtemperature for 30 minutes, diluted with 30 ml of chloroform andextracted with three 20 ml portions of saturated sodium bicarbonatesolution. The extract was dried over magnesium sulphate and concentratedto dryness. The resulting mixture of (1,2,3,4,5,12-hexahydro-5- and-12-hydroxy-7,10-dimethoxy-2-naphthacenyl) methyl ketone was dissolvedin acetic anhydride and treated at room temperature for 1 hour with 5mol equivalents of thallium (III) acetate. After the addition of 5 molequivalents of pyridine, the mixture was again stirred at roomtemperature for 1 hour, diluted with water and extracted withchloroform. The chloroform extract was washed with 2 N hydrochloric acidand saturated sodium bicarbonate solution and concentrated to dryness.Chromatography on silica gel gave2-acetyl-1,2,3,4-tetrahydro-7,10-dimethoxy-5,12-naphthacenylene-diacetateof melting poing 232°-233° C. (from hexane) in 45% yield.

A solution of 90 mg (0.9 mmol) of chromic acid in 2 ml of acetic acidwas added to a solution of 100 mg (0.22 mmol) of2-acetyl-1,2,3,4-tetrahydro-7,10-dimethoxy-5,12-naphthacenylene-diacetatein 2 ml of acetic acid. The mixture was stirred at room temperature for2 hours, diluted with chloroform and water, washed with saturated sodiumhydrogen carbonate solution, dried over magnesium sulphate andconcentrated to dryness. Recrystallisation from ethyl acetate/hexane(2:1) yielded2-acetyl-1,2,3,4,6,11-hexahydro-7,10-dimethoxy-6,11-dioxo-5,12-naphthacenylene-diacetate.

EXAMPLE 2

In a manner analogous to that described in Example 1, a mixture of1,2,3,4-tetrahydro-5,8-dimethoxy-2,3-dimethylene-1,4-epoxyanthracene andmethyl acrylate was reacted to give1,2,3,4,5,12-hexahydro-7,10-dimethoxy-5,12-epoxynaphthacene-2-carboxylicacid methyl ester which was converted via5,12-diacetoxy-1,2,3,4-tetrahydro-7,10-dimethoxy-2-naphthacenecarboxylicacid methyl ester into5,12-diacetoxy-1,2,3,4,6,11-hexahydro-7,10-dimethoxy-6,11-dioxo-2-naphthacenecarboxylicacid methyl ester.

EXAMPLE 3

A mixture of 11.4 g of2,3,5,6-tetramethylene-7-oxabicyclo[2.2.1]heptane, 2 g of anhydrous zincchloride, 30 ml of methyl vinyl ketone and 75 ml of chloroform,containing 10 mg of hydroquinone, was stirred at room temperature for 20hours under nitrogen. The mixture was concentrated under reducedpressure (ca 15 mmHg, room temperature) and rapidly eluted withmethylene chloride/ethyl acetate (2:1) on a short column filled with 18g of SiO₂ (70-230 mesh). The first fractions contained methyl(1,2,3,4,5,6,7,8-octahydro-2,3-dimethylene-1,4-epoxynaphthalene-6-yl)ketone and unreacted methyl vinyl ketone. After the addition of 5 mg ofhydroquinone, the mixture was concentrated to dryness at roomtemperature under reduced pressure (1 mmHg) until the methyl vinylketone had been completely removed. There were obtained 14.5 g (86%) ofmethyl(1,2,3,4,5,6,7,8-octahydro-2,3-dimethylene-1,4-epoxynaphthalen-6-yl)ketone in sufficient purity for the next step.

By distillation under reduced pressure there was obtained in 71% yieldpure methyl(1,2,3,4,5,6,7,8-octahydro-2,3-dimethylene-1,4-epoxynaphthalen-6-yl)ketone in the form of a colourless oil (b.p. ₀.1 120° C.) consisting ofa mixture of diastereomers (95:5).

To a solution of 11.4 g of methyl(1,2,3,4,5,6,7,8-octahydro-2,3-dimethylene-1,4-epoxynaphthalen-6-yl)ketone in 60 ml of 1,2-dimethoxyethane were added portionwise at 85° C.during 60 minutes 14.5 g of anthranilic acid in 90 ml of1,2-dimethoxyethane simultaneously with 12.3 g of pentyl nitrite in 90ml of 1,2-dimethoxyethane. The mixture was heated at 85° C. until gasevolution has ceased (20-45 minutes) and, after cooling to roomtemperature, treated with 100 ml of 10% aqueous potassium hydroxide and200 ml of ether. The aqueous phase was extracted four times with 100 mlof ether each time, the ether extract was washed four times with 100 mlof water each time, dried over sodium sulphate and concentrated. 15 mlof dipropyl ether/methanol (3:1, v/v) were added to the residue. Theprecipitate was filtered off and washed with 10 ml of the foregoingdipropyl ether/methanol mixture. 5.4 g (35%) of a mixture of 85% methyl(1,2,3,4,5,6,11,12-octahydro-5,12-epoxynaphthacen-2-yl) ketone and 15%(1,2,3,4,5,12-hexahydro-5,12-epoxynaphthacen-2-yl) methyl ketone wereobtained. The yield could be increased to 50% by chromatography of themother liquor on aluminium oxide (neutral).

A solution of 0.65 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 30ml of benzene was added to a solution of 0.8 g of the obtained accordingto the previous paragraph in 20 ml of benzene. After 3 hours at roomtemperature, the precipitate was filtered off and washed with benzene.The benzene phase was washed with 50 ml of saturated aqueous sodiumhydrogen sulphite solution and water until it had been completelydecolourised, dried over sodium sulphate and concentrated to dryness.There were obtained 754 mg (95%) of(1,2,3,4,5,12-hexahydro-5,12-epoxynaphthacen-2-yl) methyl ketone ofmelting point 158°-160° C. (from ethanol).

A mixture of 0.68 g of(1,2,3,4,5,12-hexahydro-5,12-epoxynaphthacen-2-yl) methyl ketone, 15 mlof chloroform and 0.9 ml of trifluoroacetic acid was left to stand atroom temperature for 20 hours, neutralised with sodium hydrogencarbonate and extracted with methylene chloride. The extract was driedover sodium sulphate and concentrated to dryness. The residue wastreated with 50 ml of methylene chloride, 1 ml of diethyl ether and 12 gof silicic acid and the mixture was stirred in the air for 48 hours.After concentration to dryness, the residue was chromatographed onsilicic acid. There were obtained 475 g (38%) of crude2-acetyl-1,2,3,4-tetrahydro-5,12-naphthacenedione which, after washingwith methanol, had a melting point of 189°-192° C. (from ethanol).

A mixture of 178 mg of2-acetyl-1,2,3,4-tetrahydro-5,12-naphthacenedione, 700 mg of zinc dustand 10 ml of acetic anhydride was heated at 115° C. for 40 minutes undernitrogen. The solid residue was filtered off and washed with three 10 mlportions of chloroform. Excess acetic anhydride was removed by theaddition of aqueous sodium hydrogen carbonate (3 hours stirring at 20°C.). The mixture was extracted with three 10 ml portions of chloroform,the chloroform extract was dried over sodium sulphate and concentratedto dryness. There were obtained 223 mg (98%) of crude2-acetyl-1,2,3,4-tetrahydro-5,12-naphthacenylene-diacetate. Afterwashing with 3 ml of ether, there were obtained 175 mg (77%) ofcolourless crystals of melting point 226°-229° C. (fromchloroform/ethanol).

A mixture of 221 mg of2-acetyl-1,2,3,4-tetrahydro-5,12-naphthacenylene-diacetate and 0.2 g ofchromic acid in 10 ml of 80% aqueous acetic acid was stirred at 20° C.under nitrogen for 2 hours. After the addition of 20 ml of chloroformand neutralisation with aqueous sodium hydrogen carbonate, the mixturewas extracted with three 10 ml portions of chloroform, the extract wasdried over sodium sulphate and concentrated to dryness. The crudeproduct (225 mg) was recrystallised from methanol and yielded 131 mg(55%) of2-acetyl-1,2,3,4,6,11-hexahydro-6,11-dioxo-5,12-naphthacenylene-diacetateof melting point 195°-198° C.

EXAMPLE 4

A solution of 3.38 g of1,2,3,4,8a,9,10,10a-octahydro-2,3-dimethylene-1,4-epoxyanthracene-5,8dionein 50 ml of methylene chloride and 50 ml of methanol was cooled to -70°C. and treated under nitrogen with 2.04 g of tetra-n-butylammoniumborohydride in 10 ml of methylene chloride. The mixture was then stirredat -70° C. for 1.75 hours. After the addition of 100 ml of aqueousammonium chloride solution, the solution was stirred for a further 1hour. The phases were separated, the aqueous phase was extracted twicewith 50 ml of methylene chloride each time and the combined organicphases were washed with two 100 ml portions of water and subsequentlydried over magnesium sulphate. After concentration andrecrystallisation, there were obtained 2.52 g (74%) of1,2,3,4,5,8,8a,9,10,10a-decahydro-2,3-dimethylene-1,4-epoxy-8-hydroxy-anthracen-5-oneof melting point 206°-207° C.

1.23 g of mesyl chloride were added to a solution, cooled to 0° C., of2.03 g of1,2,3,4,5,8,8a,9,10,10a-decahydro-2,3-dimethylene-1,4-epoxy-8-hydroxyanthracen-5-onein 20 ml of pyridine. The mixture was stirred at room temperature for1.5 hours, poured into 200 ml of ice/water and yielded, after filtrationand drying, 2.37 g (90%) of1,2,3,4,5,8,8a,9,10,10a-decahydro-2,3-dimethylene-1,4-epoxy-8-mesyloxyanthracen-5-oneof melting point 110° C. (with explosion).

876 mg of potassium tert.butylate were added under a nitrogen atmosphereto a solution of 2.37 g of1,2,3,4,5,8,8a,9,10,10a-decahydro-2,3-dimethylene-1,4-epoxy-8-mesyloxyanthracen-5-onein 40 ml of tetrahydrofuran, there being formed1,2,3,4,9,10-hexahydro-2,3-dimethylene-1,4-epoxyanthracen-5-ol. Afterstirring at room temperature for 1 hour, a further 877 mg of potassiumtert.butylate were added. The mixture was stirred for a further 45minutes, 1.32 ml of methyl iodide were added and the resulting mixturewas stirred for a further 1 hour. The mixture was treated with 100 ml ofaqueous ammonium chloride and extracted three times with 100 ml ofdiethyl ether each time. After washing with three 100 ml portions ofammonium chloride solution, the combined organic phases were dried overmagnesium sulphate. There were obtained 1.56 g (87%) of crude1,2,3,4,9,10-hexahydro-2,3-dimethylene-1,4-epoxy-5-methoxyanthracene ofmelting point 145°-147° C. (from methanol).

By reacting the1,2,3,4,9,10-hexahydro-2,3-dimethylene-1,4-epoxyanthracen-5-ol withbenzyl bromide in place of methyl iodide in an analogous manner, therewas obtained in good yield1,2,3,4,9,10-hexahydro-5-benzyloxy-2,3-dimethylene-1,4-epoxyanthracene.

1.24 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone were added at roomtemperature under a nitrogen atmosphere to a solution of 1.56 g of crude1,2,3,4,9,10-hexahydro-2,3-dimethylene-1,4-epoxy-5-methoxyanthracene in50 ml of benzene. After 1 hour, the suspension was filtered and thefiltrate was washed with benzene. The organic solution was washed withtwo 75 ml portions of sodium hydrogen sulphite solution and two 75 mlportions of water. The aqueous phase was extracted with 50 ml of benzeneand the combined organic solutions were dried over magnesium sulphate.After concentration, the residue was dissolved in 150 ml of diethylether, the solution was stirred with active carbon, the mixture wasfiltered and subsequently the filtrate was concentrated. Crystallisationof the residue from methanol yielded 1.09 g (70%) of1,2,3,4-tetrahydro-2,3-dimethylene-1,4-epoxy-5-methoxyanthracene ofmelting point 154°-155° C.

What is claimed:
 1. A compound of the formula ##STR15## wherein R¹represents a hydrogen atom or a hydroxy or methoxy group, R² representsa methyl or lower alkoxy group and R⁴ represents a hydrogen atom or ahydroxy, methoxy or benzyloxy group with the proviso that R¹ and R⁴ donot simultaneously represent a hydrogen atom.
 2. A compound of theformula ##STR16## wherein R¹ represents a hydrogen atom or a hydroxy ormethoxy group and R² represents a methyl or lower alkoxy group.
 3. Acompound of the formula ##STR17## wherein Ac represents an acetyl group,R¹ represents a hydrogen atom or a hydroxy or methoxy group, R²represents a methyl or lower alkoxy group and R⁴ represents a hydrogenatom or a hydroxy, methoxy or benzyloxy group.
 4. A compound of theformula ##STR18## wherein Ac represents an acetyl group, R¹ represents ahydrogen atom or a hydroxy or methoxy group and R² represents a methylor lower alkoxy group.
 5. The compound:2-Acetyl-1,2,3,4-tetrahydro-7,10-dimethoxy-5,12-naphthacenylene-diacetate.6. The compound:5,12-Diacetoxy-1,2,3,4-tetrahydro-7,10-dimethoxy-2-naphthacenecarboxylicacid methyl ester.
 7. The compound:2-Acetyl-1,2,3,4-tetrahydro-5,12-naphthacenylene-diacetate.